Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). METHODS: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. RESULTS: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. CONCLUSION: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.

Real-world evidence: Patient views on asthma in respiratory specialist clinics in America.

BACKGROUND: Approximately 30% to 50% of patients with moderate/severe asthma have inadequately controlled disease despite adherence to inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy. Data on prevalence and burden of uncontrolled asthma in specialty settings are lacking. OBJECTIVE: To evaluate the prevalence and burden of uncontrolled asthma in respiratory specialist clinics in the United States. METHODS: Adults with physician-diagnosed asthma attending pulmonary and allergy clinics with self-reported ICS use in the previous 4 weeks completed an electronic questionnaire including the Asthma Control Test and St George's Respiratory Questionnaire. Additional information was collected using an electronic case report form. RESULTS: Of 774 patients attending 12 pulmonary and 12 allergy clinics, 53% were not well controlled (mean [SD] Asthma Control Test, 14.3 [3.6] vs 22.4 [1.6] in well-controlled patients). Among ICS/LABA users, 56% were not well controlled, which increased with increasing ICS dose (low-dose 45.7%; high-dose 59.7%). The not well-controlled group reported more respiratory illnesses, more comorbidities, and poorer health-related quality of life (mean [SD] St George's Respiratory Questionnaire, 46.1 [18.9] vs 19.8 [12.9] in the well-controlled group). These patients also had more asthma exacerbations (≥1 exacerbation, 68.9% vs 43.1%) and increased health care resource utilization (≥1 asthma-related hospitalization, 10.7% vs 2.7%); 27.3% were also receiving systemic corticosteroids. Approximately 40% of the population were eligible for step-up to ICS/LABA/long-acting muscarinic antagonist triple therapy, and 20% were eligible for biologic therapy. CONCLUSION: Substantial unmet needs exist among patients with inadequately controlled asthma managed in United States specialist settings, which may be addressed by improved patient and physician education, better guideline implementation, and improved adherence.

Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.

PURPOSE: Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary-care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome-identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs). METHODS: First, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004-2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm-identified and questionnaire-confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate). RESULTS: For AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire-confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm-identified cases. CONCLUSIONS: AMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire-validated AMI and stroke cases yield IRRs closest to the best estimate.

Assessing the incidence of osteosarcoma among teriparatide users based on Medicare Part D and US State Cancer Registry Data.

PURPOSE: During preclinical testing, teriparatide caused a dose-dependent increase in the incidence of osteosarcoma in rats. This study compared the incidence rate of osteosarcoma among patients aged ≥65 years treated with teriparatide vs a matched-comparator cohort. METHODS: This population-based comparative-cohort study matched exposure details for each teriparatide user, identified via Medicare Part D prescription claims, and up to four comparators based on age, sex, zip code, date of claim for filled prescription, and number of unique therapeutic classes dispensed. Outcomes were identified via linkage with participating cancer registries. All US state cancer registries were invited to participate. RESULTS: Overall, 153 316 patients in the teriparatide cohort and 613 247 in the comparator cohort were linked to 811 osteosarcoma cases from 26 participating state cancer registries (68% of US patients aged ≥65 years diagnosed 2007-2014). Analysis on a subset of cohorts revealed they were balanced for known osteosarcoma risk factors and Charlson comorbidity index. Mean duration of teriparatide treatment was 10 months. No osteosarcoma cases were observed in the teriparatide cohort; the incidence rate in the comparator cohort was consistent with the background incidence rate among adults aged ≥65 years. The incidence rate ratio was 0.0 (95% confidence interval, 0.0-3.2). CONCLUSIONS: For US patients aged ≥65 years, incidence of osteosarcoma among those treated with teriparatide ranges from 0 to 3.2 times the incidence of osteosarcoma in those treated with other medications. Given low incidence of osteosarcoma, this range of effect is inconsistent with a large absolute increase in osteosarcoma risk.

Predictors of Response Outcomes for Research Recruitment Through a Central Cancer Registry: Evidence From 17 Recruitment Efforts for Population-Based Studies.

When recruiting research participants through central cancer registries, high response fractions help ensure population-based representation. We conducted multivariable mixed-effects logistic regression to identify case and study characteristics associated with making contact with and obtaining cooperation of Utah cancer cases using data from 17 unique recruitment efforts undertaken by the Utah Cancer Registry (2007-2016) on behalf of the following studies: A Population-Based Childhood Cancer Survivors Cohort Study in Utah, Comparative Effectiveness Analysis of Surgery and Radiation for Prostate Cancer (CEASAR Study), Costs and Benefits of Follow-up Care for Adolescent and Young Adult Cancers, Study of Exome Sequencing for Head and Neck Cancer Susceptibility Genes, Genetic Epidemiology of Chronic Lymphocytic Leukemia, Impact of Remote Familial Colorectal Cancer Risk Assessment and Counseling (Family CARE Project), Massively Parallel Sequencing for Familial Colon Cancer Genes, Medullary Thyroid Carcinoma (MTC) Surveillance Study, Osteosarcoma Surveillance Study, Prostate Cancer Outcomes Study, Risk Education and Assessment for Cancer Heredity Project (REACH Project), Study of Shared Genomic Segment Analysis and Tumor Subtyping in High-Risk Breast-Cancer Gene Pedigrees, Study of Shared Genomic Segment Analysis for Localizing Multiple Myeloma Genes. Characteristics associated with lower odds of contact included Hispanic ethnicity (odds ratio (OR) = 0.34, 95% confidence interval (CI): 0.27, 0.41), nonwhite race (OR = 0.46, 95% CI: 0.35, 0.60), and younger age at contact. Years since diagnosis was inversely associated with making contact. Nonwhite race and age ≥60 years had lower odds of cooperation. Study features with lower odds of cooperation included longitudinal design (OR = 0.50, 95% CI: 0.41, 0.61) and study brochures (OR = 0.70, 95% CI: 0.54, 0.90). Increased odds of cooperation were associated with including a questionnaire (OR = 3.19, 95% CI: 1.54, 6.59), postage stamps (OR = 1.60, 95% CI: 1.21, 2.12), and incentives (OR = 1.62, 95% CI: 1.02, 2.57). Among cases not responding after the first contact, odds of eventual response were lower when >10 days elapsed before subsequent contact (OR = 0.71, 95% CI: 0.59, 0.85). Obtaining high response is challenging, but study features identified in this analysis support better results when recruiting through central cancer registries.

The experience of accommodating privacy restrictions during implementation of a large-scale surveillance study of an osteoporosis medication.

PURPOSE: To explore whether privacy restrictions developed to protect patients have complicated research within a 15-year surveillance study conducted with US cancer registries. METHODS: Data from enrolling 27 cancer registries over a 10-year period were examined to describe the amount of time needed to obtain study approval. We also analyzed the proportion of patients that completed a research interview out of the total reported by the registries and examined factors thought to influence this measure. RESULTS: The average length of the research review process from submission to approval of the research was 7 months (range, <1 to 24 months), and it took 6 months or more to obtain approval of the research at 41% of the cancer registries. Most registries (78%) required additional permission steps to gain access to patients for research. After adjustment for covariates, the interview response proportion was 110% greater (ratio of response proportion = 2.1; 95% confidence interval: 1.3, 3.3) when the least restrictive versus the most restrictive permission steps were required. An interview was more often completed for patients (or proxies) if patients were alive, within a year of being diagnosed, or identified earlier in the study. CONCLUSIONS: Lengthy research review processes increased the time between diagnosis and provision of patient information to the researcher. Requiring physician permission for access to patients was associated with lower subject participation. A single national point of entry for use of cancer registry data in health research is worthy of consideration to make the research approval process efficient. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

Physician Awareness of the Safe Use of Cyproterone Acetate in Europe: A Survey on the Effectiveness of Additional Risk Minimization Measures.

BACKGROUND: Cyproterone acetate (CPA) is a synthetic progesterone derivative introduced in the 1970s and prescribed as antiandrogenic therapy for inoperable prostate cancer, sexual deviations in men, and signs of androgenization in women. In 2020, the CPA summary of product characteristics (SmPC) was revised to include an updated special warning and precaution about (1) the risk of meningioma with increasing cumulative dose and (2) contraindication in patients with meningioma or history of meningioma. A Direct Healthcare Professional Communication (DHPC) was distributed. The European Medicine Agency's Pharmacovigilance Risk Assessment Committee requested that marketing authorization holders in Europe conduct a survey to assess physicians' knowledge of the updated key safety information. The primary objective of this study was to measure physicians' awareness (i.e., did they receive and review the revised SmPC and DHPC) and level of knowledge and understanding of the key safety information pertaining to the restricted use of CPA monotherapy because of the risk of meningioma. METHODS: This cross-sectional web-based survey was administered to dermatologists, endocrinologists, gynecologists, urologists, oncologists, psychiatrists, and general practitioners in France, Germany, Poland, Spain, and the Netherlands who had prescribed CPA monotherapy in the previous 12 months to assess awareness of the risk of meningioma associated with CPA monotherapy. RESULTS: Of the 613 physicians who participated, 85% correctly indicated that CPA monotherapy should be prescribed with the lowest effective dose, 75% correctly indicated that the risk of meningioma increases with increasing cumulative CPA monotherapy doses, and 73% correctly indicated that treatment with CPA-containing products must be stopped permanently if a patient is diagnosed with meningioma. Overall, 40% of physicians reported having received the DHPC, and 42% reported having received the revised SmPC. CONCLUSIONS: Despite low recall of receipt of the updated SmPC and DHPC, most physicians surveyed are aware of the meningioma risk and actions to mitigate the risk.

Post-Authorization Safety Studies of Acute Liver Injury and Severe Complications of Urinary Tract Infection in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: At the time of dapagliflozin's approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. OBJECTIVE: To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012-February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. RESULTS: In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59-1.24) and for sUTI was 0.76 (0.60-0.96) in females and 0.74 (0.56-1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. CONCLUSIONS: These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.

Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. OBJECTIVE: The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. RESULTS: In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22-0.86]; HIRD, 0.76 [95% CI, 0.62-0.93]; Medicare, 0.69 [95% CI, 0.59-0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62-0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. CONCLUSIONS: This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. STUDY REGISTRATION: European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.

Teriparatide and Osteosarcoma Risk: History, Science, Elimination of Boxed Warning, and Other Label Updates.

The phase 3 trials of the bone anabolic drug teriparatide were prematurely terminated because of a preclinical finding of osteosarcoma in rats treated with high doses of teriparatide for near lifetime. Even so, results from these and subsequent clinical trials showed efficacy and tolerability. Based on the phase 3 results and additional preclinical investigations, Forteo (teriparatide) was approved for use in the United States with an indication for the treatment of osteoporosis in patients at high risk for fracture, a boxed warning regarding potential risk of osteosarcoma, a 2-year lifetime limitation of use, other risk mitigations, and a requirement to assess for risk of osteosarcoma in humans treated with teriparatide. Subsequent investigations included five real-world studies directed at assessing a connection between teriparatide and osteosarcoma risk in humans. The early studies did not identify an increased risk of osteosarcoma but were inadequate to sufficiently characterize risk, given the low incidence of this rare form of bone cancer. Learning from these efforts, two studies were undertaken using claims data to identify large cohorts of patients treated with teriparatide and assess whether these patients were found to have osteosarcoma by linking pharmacy claims data with data from cancer registries. These studies showed no increase in osteosarcoma in patients using teriparatide compared with unexposed groups, as well as to the expected population-based background incidence of the disease. Based on this real-world evidence and the totality of data collected from postmarketing use and other clinical investigations, the label was updated in 2020. The changes included addition of information from large observational studies using real-world evidence, removal of the boxed warning, and a revision of the 2-year lifetime limitation. Thus, observational studies with large sample sizes using real-world data can provide supportive evidence to facilitate regulatory decisions including the elimination of a boxed warning. © 2022 Eli Lilly and Company. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Risk of Major Cardiovascular and Cerebrovascular Events in Users of Lisdexamfetamine and Other Medications for Attention-Deficit/Hyperactivity Disorder in Denmark and Sweden: A Population-Based Cohort Study.

INTRODUCTION: This study aimed to estimate risks of cardiovascular and cerebrovascular events in patients treated with lisdexamfetamine dimesylate (LDX) compared with patients previously treated with other attention-deficit/hyperactivity disorder (ADHD) medications (amphetamine, dexamphetamine, methylphenidate or atomoxetine). METHODS: This population-based cohort study used data from Danish and Swedish medical and administrative national registers. The LDX cohort included adult patients initiating LDX with at least 12 months' data preceding first LDX dispensing (index date). A random sample of patients treated with at least one non-LDX ADHD medication in the 6-24 months (but not less than 6 months) before index date (previous-users cohort) were matched to LDX users on age, sex, region and calendar year. The primary outcome, a composite of major adverse cardiovascular and cerebrovascular events (MACE), included first hospitalisation for acute myocardial infarction or stroke and out-of-hospital coronary heart disease or cerebrovascular disease death. Incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) of MACE were estimated using Poisson regression. RESULTS: From Denmark/Sweden, 5516/40,163 LDX users and 27,494/200,389 previous users were included. In Denmark, IRs of MACE/1000 person-years (95% CI) were similar for LDX (1.63 [0.85-3.14]) and previous users (1.61 [1.28-2.01]). In Sweden, IRs (95% CI) were 1.40 (1.09-1.79) in LDX users and 1.17 (1.00-1.38) in previous users. Adjusted MACE IRRs (95% CI) for LDX versus previous use were 1.01 (0.48-2.13) in Denmark, 1.13 (0.75-1.71) in Sweden, and 1.10 (0.77-1.58) in the pooled analysis. CONCLUSION: Our findings suggest little to no increased risk of cardiovascular and cerebrovascular events in patients treated with LDX compared with patients previously treated with other ADHD medications.

Teriparatide Did Not Increase Adult Osteosarcoma Incidence in a 15-Year US Postmarketing Surveillance Study.

The Osteosarcoma Surveillance Study was initiated in the United States in 2003 to monitor for a potential association between the osteoporosis treatment teriparatide and osteosarcoma. Osteosarcoma occurs at a background incidence rate of approximately 2.5 cases per million per year in US adults aged 40 years or older. For this study, incident cases of osteosarcoma diagnosed between January 1, 2003, and December 31, 2016, were identified through participating cancer registries in the United States. Information on prior exposure to medications and possible risk factors was obtained by self-report (or proxy report) in telephone interviews. Exposure information was verified through medical record abstraction for a sample of patients. A standardized incidence ratio was estimated to compare the observed and expected numbers of osteosarcoma patients with a prior history of teriparatide treatment. Interviews were completed for 24% (1173) of patients diagnosed with osteosarcoma between 2003 and 2016; three reports of teriparatide use before diagnosis were identified. Based on the background incidence rate, the expected number of osteosarcoma cases among patients treated with teriparatide was 4.17. Given the three observed cases, the standardized incidence ratio was 0.72 (90% confidence interval [CI], 0.20 to 1.86). Demographic characteristics were similar for interviewed and noninterviewed patients. Agreement was >90% between self-reported and chart-recorded exposure to osteoporosis medications. Mean age of interviewed patients was 61 years; 53% of patients were male, 84% were white, and 5% were Hispanic. The prevalence of suspected risk factors for development of osteosarcoma among the osteosarcoma cohort was 19% for history of radiation and 4% for history of Paget's disease of bone. These findings showed that the incidence of osteosarcoma associated with teriparatide use during the 15-year surveillance period was no different than would be expected based on the background incidence rate of osteosarcoma. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Identification and Validation of Major Cardiovascular Events in the United Kingdom Data Sources Included in a Multi-database Post-authorization Safety Study of Prucalopride.

INTRODUCTION: A multinational post-authorization safety study assessed cardiovascular safety in initiators of prucalopride for chronic constipation compared with a matched cohort of polyethylene glycol 3350 initiators. The primary safety outcome was major adverse cardiovascular events (MACE), a composite of hospitalization for acute myocardial infarction, stroke, or in-hospital cardiovascular death. We report the validation process for MACE endpoints in United Kingdom (UK) data sources: Clinical Practice Research Datalink (CPRD GOLD), The Health Improvement Network (THIN), and the Information Services Division (ISD) Scotland. METHODS: Modified electronic algorithms from prior research identified potential MACE cases. Validation followed a common protocol, adapted for each database, with all information anonymized: (1) direct confirmation via linkage to hospital records (CPRD GOLD); (2) requests for additional clinical information through questionnaires (CPRD GOLD), free-text (THIN), or abstraction of hospital records (ISD); (3) manual review of electronic records of potential events retrieved by the algorithm (CPRD GOLD/THIN); and (4) event adjudication by three clinicians, blinded to exposure, for all remaining events. RESULTS: Electronic algorithms identified 260 potential MACE cases: 38 confirmed via linkage to hospital records (CPRD GOLD), 56 ruled out as non-cardiovascular death cases (THIN), and three unavailable for review (ISD), leaving 163 potential cases. After manual review with additional information (steps 2 and 3), 45 were considered noncases (CPRD GOLD/THIN). Upon final adjudication (step 4), remaining potential events were adjudicated as definite (n = 62), probable (n = 10), possible (n = 13), or noncases (n = 33). CONCLUSIONS: Given the limitations of relying solely on computer algorithms to identify cardiovascular outcomes, validation with clinical review is essential to guide interpretation.

Status of asthma control in pediatric primary care: results from the pediatric Asthma Control Characteristics and Prevalence Survey Study (ACCESS).

OBJECTIVE: To estimate the prevalence of uncontrolled asthma in pediatric patients with asthma visiting their primary care provider for any medical reason. STUDY DESIGN: This was a cross-sectional survey conducted at 29 pediatric care sites across the United States. Children age 4-17 years with self- or caregiver-reported asthma completed the Childhood Asthma Control Test (C-ACT) or the Asthma Control Test (ACT) and responded to demographic and health-related questions. Uncontrolled asthma was defined as a C-ACT or ACT score

Predictors of uncontrolled asthma in adult and pediatric patients: analysis of the Asthma Control Characteristics and Prevalence Survey Studies (ACCESS).

BACKGROUND: Despite the availability of effective asthma treatments and evidence-based management guidelines focusing on asthma control, many patients have asthma that is inadequately controlled. The objective of this analysis was to identify risk factors for uncontrolled asthma among adult and pediatric patients. METHODS: Two cross-sectional surveys assessing asthma control status were conducted between January 25 and May 2, 2008, among adult and pediatric patients with asthma. Participants completed a self-administered questionnaire including demographics, medical history, and current asthma medication use. In addition, participants completed either the Asthma Control Test (ACT) or Childhood ACT (C-ACT). Uncontrolled asthma was defined as a score of < or = 19 on the ACT or C-ACT. Multiple logistic regression was used to identify factors related to uncontrolled asthma. RESULTS: A sample of 64 primary care provider sites (35 for adults and 29 for pediatric patients) across the United States enrolled. One study enrolled 2238 adults (aged > or = 18 years) and the other 2429 children (aged 4-17 years) with asthma. The patients were visiting their health care provider for a scheduled appointment for any reason. The overall prevalence of uncontrolled asthma was 58% and 46% in adult and pediatric patients, respectively. Multivariate analysis identified predictors of uncontrolled asthma in both adults and children including self-reported asthma severity, lack of adherence, and recent history of cold, flu, or sinus infection. The predictors of uncontrolled asthma seen only in adults were less education, insurance status, current smoker, body mass index (BMI) >30 kg/m(2), and history of gastroesophageal symptoms. The predictors of uncontrolled asthma seen only in children were female aged 12-17 years, caregiver unemployment, and history of asthma exacerbation. CONCLUSIONS: A high proportion of patients with asthma seen in primary care settings are not well controlled. Recognition of specific predictors can signal who may be at higher risk of uncontrolled asthma and provide the opportunity for early interventions.

No Evidence of Off-label Use of Olodaterol and Indacaterol in Denmark, France, and the Netherlands: A Drug Utilization Study.

To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.

Effect of ropinirole on sleep outcomes in patients with restless legs syndrome: meta-analysis of pooled individual patient data from randomized controlled trials.

STUDY OBJECTIVE: To compare the effects of ropinirole with those of placebo on sleep, as evaluated by specific domains of the Medical Outcomes Study (MOS) sleep scale, as well as the Clinical Global Impression-Improvement (CGI-I) scale, in patients with restless legs syndrome (RLS). DESIGN: Meta-analysis of six randomized, double-blind, placebo-controlled, parallel-group trials conducted in the United States and Europe. PATIENTS: A total of 1679 patients aged 18-79 years with primary moderate-to-severe RLS who received ropinirole (835 patients) or placebo (844 patients). MEASUREMENTS AND MAIN RESULTS: A systematic review of MEDLINE (January 1980-January 2007) and clinical trial registers was performed to identify placebo-controlled trials of ropinirole that used the 12-item MOS sleep scale to assess sleep in patients with RLS. Individual patient data from both published and nonpublished trials were pooled for meta-analysis. In the eligible studies, immediate-release ropinirole 0.25-6 mg or placebo had been given for at least 12 weeks. In addition, sleep scale summary scores for the domains of sleep quantity, adequacy, disturbance, and daytime somnolence had to have been assessed at baseline and at 12 weeks. Our meta-analysis found that at baseline study patients slept an average of 5.8 hours/night. At the end of 12 weeks, ropinirole-treated patients slept a mean of 2.5 hours/week more and had a 21% greater improvement from baseline in sleep adequacy scores compared with patients receiving placebo. Ropinirole-treated patients also had 14% less sleep disturbance and 8% less daytime somnolence than patients receiving placebo. Clinicians rated 63% of ropinirole-treated patients and 47% of patients receiving placebo as responders based on the CGI-I scale. Mixed effects analysis of covariance was used to estimate treatment effect adjusting for study center as a random effect, as well as the following fixed effects known to affect sleep: baseline sleep characteristics, age, sex, and chronic medical conditions. All differences were statistically significant (p<0.05), even after adjusting for multiple comparisons. CONCLUSION: Pooled data from six similarly designed clinical trials provide evidence that ropinirole improves sleep quantity and adequacy, and lessens sleep disturbance and daytime somnolence in patients with primary RLS.

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study.

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36-1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350.

INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.

The ATTEMPT cohort: a multi-national longitudinal study of predictors, patterns and consequences of smoking cessation; introduction and evaluation of internet recruitment and data collection methods.

AIMS: The ATTEMPT study was designed to chart the natural history of smoking cessation and associated short-term health outcomes and effects on medical resource utilization among a cohort recruited across multiple countries. This paper describes the methods for recruitment and follow-up, the baseline population characteristics of the enrolled population and 1-year response rates. DESIGN: ATTEMPT is a multi-national prospective cohort study that used the internet for subject recruitment and online assessments every 3 months for 2.5 years. SETTING: Subjects were recruited via e-mail from existing internet panels [Canada (n = 208), France (n = 201), the United Kingdom (n = 200) and the United States (n = 1400]. SUBJECTS: Panel members who were aged 35-65 years, smoked at least five cigarettes per day and at initiation stated an intention to quit smoking within the next 3 months were eligible for this study. MEASUREMENTS: Measures included: attempts to quit, smoking status, smoking history, nicotine dependence and craving, methods used to quit smoking, reasons for quitting or failing to quit smoking, short-term health effects, health resource utilization, wellbeing, concern over weight gain, confidence in preventing weight gain, body weight and demographics. In addition, in-home assessments of weight were undertaken by field staff for a random sample of US participants. FINDINGS: Country-specific recruitment was completed within 17 days. The recruitment method produced a sample with characteristics broadly similar to those found in national surveys of smokers except for higher prevalence of obesity in the US and Canadian samples and higher educational level. At the end of 1 year the response rate was 52%, and there was little evidence of differential loss to follow-up by key subject characteristics. Weight reported in the survey was found to correlate highly with weight measured during in-home visits. CONCLUSION: This paper demonstrates the feasibility of enrolling and following a diverse cohort of smokers for self-reported health and behaviour measures via the internet.